Prostate-Specific Membrane Antigen (PSMA) Expression Predicts Need for Early Treatment in Prostate Cancer Patients Managed with Active Surveillance

Abstract

Metabolic dysregulation is an early event in carcinogenesis. Here, we examined the expression of enzymes involved in de novo lipogenesis (ATP-citrate lyase: ACLY), glucose uptake (Glucose Transporter 1: GLUT1), and folate-glutamate metabolism (Prostate-Specific Membrane Antigen: PSMA) as potential biomarkers of risk for early prostate cancer progression. Patients who were managed initially on active surveillance with a Gleason score of 6 or a low-volume Gleason score of 7 (3 + 4) were accrued from a prostate cancer diagnostic assessment program. Patients were asked to donate their baseline diagnostic biopsy tissues and permit access to their clinical data. PSMA, GLUT1, and ACLY expression were examined with immunohistochemistry (IHC) in baseline biopsies, quantitated by Histologic Score for expression in benign and malignant glands, and compared with patient time remaining on active surveillance (time-on-AS). All three markers showed trends for elevated expression in malignant compared to benign glands, which was statistically significant for ACLY. On univariate analysis, increased PSMA and GLUT1 expression in malignant glands was associated with shorter time-on-AS (HR: 5.06, [CI 95%: 1.83-13.94] and HR: 2.44, [CI 95%: 1.10-5.44], respectively). Malignant ACLY and benign gland PSMA and GLUT1 expression showed non-significant trends for such association. On multivariate analysis, overexpression of PSMA in malignant glands was an independent predictor of early PC progression (p = 0.006). This work suggests that the expression of metabolic enzymes determined by IHC on baseline diagnostic prostate biopsies may have value as biomarkers of risk for rapid PC progression. PSMA may be an independent predictor of risk for progression and should be investigated further in systematic studies.

Keywords: ACLY; GLUT1; PSMA; active surveillance; progression; prostate cancer.

Figure 1

Patterns of marker expression in prostate biopsies. (a) Representative images (10× magnification) showing heterogeneous PSMA expression but uniform GLUT1 and ACLY expression in prostate glands. Mild expression for GLUT1 and strong expression for ACLY are shown in this representative case. (Black arrows point to moderate to strong marker expression, blue arrows for mild marker expression, and yellow arrows point to no expression). (b,c) Magnified views of images in (a).

Figure 2

Enhanced PSMA, GLUT1, and ACLY expression in malignant prostate glands compared to benign glands. Prostate biopsy tissue, including benign and malignant components (40× magnification). (a) Prostate biopsy tissue of a 71-year-old patient, GS = 3 + 3 = 6 (ISUP Grade Groupe 1), reveals higher PSMA expression in prostate adenocarcinoma compared to benign epithelial cells. (b) Prostate biopsy tissue of a 73-year-old patient, GS = 3 + 4 = 7 (ISUP Grade Groupe 2), shows enhanced GLUT1 expression in prostate adenocarcinoma compared to benign epithelial cells. (c) Prostate biopsy tissue of a 76-year-old patient, GS = 3 + 3 = 6 (ISUP Grade Groupe 1), reveals enhanced ACLY expression in malignant glands compared to benign glands. (d) Graphs illustrate average H-scores of PSMA, GLUT1, and ACLY IHC expression in benign and malignant glands for the entire group of patients (error bars are SEM, * = p-value 0.04).

Figure 3

Association of marker expression in malignant prostatic glands with time patients remained on active surveillance (time-on-AS). (40× magnification) (a) Images on the left: 64-year-old patient, GS = 3 + 4 = 7 (ISUP grade group 2), revealing low tumoral PSMA expression with a long time-to-progression (124.1 months). Images on the right: 75-year-old patient, GS = 3 + 4 = 7 (ISUP grade group 2), revealing tumoral PSMA overexpression with a short time to progression (16.1 months). (b) Images on the Left: 64-year-old patient, GS = 3 + 4 = 7 (ISUP grade group 2), revealing low tumoral GLUT1 expression with a long time to progression (124.1 months). Images on the Right: 75-year-old patient, GS = 3 + 4 = 7 (ISUP grade group 2), revealing tumoral GLUT1 overexpression with a short time to progression (22.2 months). (c) Images on the Left: 84-year-old patient, GS = 3 + 3 = 6 (ISUP grade group 1), revealing low tumoral ACLY expression with a long time to progression (75.6 months). Images on the Right: 76-year-old patient, GS = 3 + 3 = 6 (ISUP grade group 1), revealing tumoral ACLY overexpression with a very short time to progression (2.8 months). Kaplan–Meier survival curves in relation to marker expression in the malignant components of prostate biopsies.

Figure 3

Association of marker expression in malignant prostatic glands with time patients remained on active surveillance (time-on-AS). (40× magnification) (a) Images on the left: 64-year-old patient, GS = 3 + 4 = 7 (ISUP grade group 2), revealing low tumoral PSMA expression with a long time-to-progression (124.1 months). Images on the right: 75-year-old patient, GS = 3 + 4 = 7 (ISUP grade group 2), revealing tumoral PSMA overexpression with a short time to progression (16.1 months). (b) Images on the Left: 64-year-old patient, GS = 3 + 4 = 7 (ISUP grade group 2), revealing low tumoral GLUT1 expression with a long time to progression (124.1 months). Images on the Right: 75-year-old patient, GS = 3 + 4 = 7 (ISUP grade group 2), revealing tumoral GLUT1 overexpression with a short time to progression (22.2 months). (c) Images on the Left: 84-year-old patient, GS = 3 + 3 = 6 (ISUP grade group 1), revealing low tumoral ACLY expression with a long time to progression (75.6 months). Images on the Right: 76-year-old patient, GS = 3 + 3 = 6 (ISUP grade group 1), revealing tumoral ACLY overexpression with a very short time to progression (2.8 months). Kaplan–Meier survival curves in relation to marker expression in the malignant components of prostate biopsies.